The Baltimore Longitudinal Study of Aging (BLSA) prostate aging and disease study has both retrospective and prospective arms involving repeated assessments of anatomical, physiological, hormonal, and behavioral aspects of age-associated changes in prostate size. The retrospective arm of the study examines the sex steroid and PSA levels from frozen sera stored during the three most recent visits and visits closest to 10, 15, 20 and 25 years before study initiation. The prospective arm involves male BLSA participants and has continued for more than 15 years. Data collection was on hold starting in December 2002, and was restarted in approximately August 2005. [unreadable] Our previous work suggests that prostate cancer develops over a period of at least 10 years in most men, and that PSA can stratify men at risk as long as 20 to 30 years prior to diagnosis. These observations argue that there is a long period in the development of prostate cancer, where preventive strategies might decrease the risk for prostate cancer and perhaps for better identifying men where the prostate cancer might be life threatening. Our work has contributed to examining what are potential risk factors for prostate cancer. Over the past year, we have continued to examine potential risks, and have directed a new effort to focus on whether the identification of life threatening prostate cancer can be made early in the development of disease. [unreadable] In the past year, one study was published which examined the relationship of serum testosterone levels and the development of prostate cancer. The study is of particular interest as a potential risk of testosterone replacement therapy is an increase in the incidence of prostate cancer. It is unclear whether higher levels of serum testosterone are associated with a higher risk of prostate cancer. To address this issue, we prospectively evaluated serum androgen concentrations and prostate cancer risk in 794 BLSA men. Higher free testosterone was associated with an increased age-adjusted risk of prostate cancer {RRs by quartile: 1.00, 1.52 [95% confidence interval (95% CI), 0.93-2.50], 1.16 (95% CI, 0.61-2.20), 2.59 (95% CI, 1.28-5.25); P(trend) = 0.03}, which persisted after excluding measures in men less than 45 years of age [RRs by quartile: 1.00, 1.33 (95% CI, 0.78-2.25), 1.26 (95% CI, 0.68-2.33), 1.89 (95% CI, 0.99-3.61); P(trend) = 0.03]. Compared to men with eugonadal FTI (greater than or equal to 0.153), men with hypogonadal FTI had a decreased risk of prostate cancer (RR, 0.51; 95% CI, 0.31-0.82). The observations suggest that higher levels of free testosterone are associated with an increased risk of prostate cancer, and that men receiving testosterone therapy should be regularly monitored for prostate cancer.[unreadable] The second area of prostate cancer investigation has been to examine whether there are differences in men who developed life threatening prostate cancer that can be detected during clinical evaluation at a time when the cancer should be curable. Prostate specific antigen (PSA) is widely used to screen for prostate cancer because cancers detected by PSA screening are discovered at an earlier stage than without screening. Clinicians generally agree that PSA screening can detect early stage cancers and that some of these are destined to metastasize. However, the PSA level or threshold value at which further evaluation with a prostate biopsy should be recommended remains controversial. A manuscript has recently been accepted by the Journal of the National Cancer Institute addressing this issue. The focus of the analysis was whether the rate of change in PSA (i.e. PSA velocity) may be an important indicator of the presence of life threatening disease. PSA velocity was determined in 980 men (856 without prostate cancer; 104 with prostate cancer who were alive or died of another cause; 20 who died of prostate cancer) over 3 decades. PSA velocity measured 10-15 years before diagnosis (when most men had PSA levels below 4.0ng/ml) predicted cancer specific survival 25 years later; survival was 92 percent (95% CI = 84 to 96) when PSA velocity was less than 0.35 ng/ml per year and 54 percent (95% CI = 15 to 82) when PSAV was >0.35 ng/ml per year (P=0.0001). As compared to those with a PSA velocity less than 0.35ng/ml per year, the relative risk of prostate cancer death was 4.7 (95% CI = 1.3 to 16.5) when PSAV was >0.35ng/ml per year (P=.016). The conclusion from the study was that at a time when PSA levels indicate the presence of curable prostate cancer, PSAV may help identify men with life threatening disease. Currently, we are extending this concept by asking whether using a man?s cumulative PSA history can improve the assessment of future risk of having a life-threatening prostate cancer. Using a simple additive approach where at each evaluation the health care provider sums the number of PSA evaluations where the patient has met a simple rule, the probability of having or developing a life threatening prostate cancer can be estimated. For example, a man over the age of 40 who never meets the rule of having a PSA velocity greater than 0.2 mg/year, will have approximately a 2-4% probability of developing a life-threatening prostate cancer, while a man who has met this rule on 5 consecutive yearly evaluations has a risk of 19% (CI=8-35%), despite the likelihood that his PSA is still quite normal. [unreadable] Benign prostatic hyperplasia poses a significant public health problem, but its etiology remains unclear, and potential risk factors have not been clearly identified. Obesity and associated abnormalities in glucose homeostasis may play a role in benign prostatic hyperplasia development by influencing prostate growth. We examined whether obesity, fasting plasma glucose concentration, and diabetes are associated with radiologically determined prostate enlargement, an objective measure of benign prostatic hyperplasia. The study included 422 BLSA men who had total prostate volume measured by pelvic magnetic resonance imaging, 91 (21.6%) of whom had prostate enlargement (defined as total prostate volume greater or equal to 40 cc) at first prostate MRI evaluation. Compared with men of normal weight [body mass index (BMI) less than 25 kg/m(2)], the age-adjusted odds ratio (OR) for prostate enlargement for overweight men (BMI, 25-29.9 kg/m(2)) was 1.41 (95% CI, 0.84-2.37), for obese men (BMI, 30-34 kg/m(2)) was 1.27 (95% CI, 0.68-2.39), and for severely obese men (BMI greater than or equal to 35 kg/m(2)) was 3.52 (95% CI, 1.45-8.56) (P = 0.01). Men with elevated fasting glucose (greater than 110 mg/dl) were more likely to have an enlarged prostate than men with normal fasting glucose (less than or equal to 110 mg/dl) (OR, 2.98; 95% CI, 1.70-5.23), as were men with a diagnosis of diabetes (OR, 2.25; 95% CI, 1.23-4.11). The observations suggest that obesity, elevated fasting plasma glucose, and diabetes are risk factors for benign prostatic hyperplasia.[unreadable] At this time, we are continuing to examine factors that contribute to prostate growth and the development of cancer, and strategies for early diagnosis of prostate disease with a focus on the identification of risk for high risk cancers. In the coming year, we are planning an examination of a new marker for prostate cancer, and to begin a study of the genetic characteristics for the development of high risk prostate cancer.